Interim Safety Analysis of a Phase 2 Randomized Study of Daratumumab (Dara), Lenalidomide (R), Bortezomib (V), and Dexamethasone (d; Dara-Rvd) Vs. Rvd in Patients (Pts) with Newly Diagnosed Multiple Myeloma (MM) Eligible for High‐Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)

Background: Addition of Dara to Vd and Rd improved complete (CR) and overall response rates (ORR) and progression‐free survival (PFS) in relapsed MM. RVd followed by HDT, ASCT, and consolidation RVd achieves high response rates in previously untreated MM. The primary objective of this study is to determine if the addition of Dara to RVd will increase the stringent CR (sCR) rate by the end of post‐ASCT consolidation therapy.

Methods: This is an ongoing multicenter, randomized, open‐label, active‐controlled study conducted in the US. Key eligibility criteria include age 18‐70 years; eligibility for HDT and ASCT; documented MM per IMWG 2015 criteria; ECOG performance score of 0‐2; and no prior systemic therapy for MM. An initial safety run-in phase was performed in 16 pts treated with Dara-RVd in order to assess potential dose limiting toxicities (DLTs) during Cycle 1. Following successful completion of the safety run-in phase, approximately 200 pts will be randomized 1:1 to Dara‐RVd or RVd. Pts receive 4 induction cycles (every 21 days) of RVd +/‐ Dara; followed by stem cell mobilization, HDT, ASCT; 2 consolidation cycles (every 21 days) of RVd +/‐ Dara; and maintenance therapy with R +/‐ Dara for 24 months. During induction and consolidation (cycles 1‐6), all pts receive R 25 mg orally on Days 1‐14; V 1.3 mg/m² subcutaneously on Days 1, 4, 8, and 11; and d 40 mg weekly. In the Dara‐RVd group, Dara 16 mg/kg IV is given on Days 1, 8, and 15 of cycles 1‐4 and on Day 1 of cycles 5‐6. During maintenance (cycles 7-32), all pts receive R 10 mg daily (15 mg beginning at Cycle 10 if no tolerability issues) on Days 1‐21 every 28 days; Dara 16 mg/kg IV is given every 56 days (every other cycle) in the Dara‐RVd arm only. Here, we present the results of the pre-planned safety analysis after the first 4 cycles of therapy in the safety run-in phase of the study.

Results: Sixteen pts were enrolled in the safety run-in, and all pts had completed at least 4 cycles of Dara-RVd as of 05 July 2017. Median age was 62.5 (range 46 to 65) years, and 50% were male. Thirteen percent of pts were ISS stage II and stage III, each. Most pts (63%) were ECOG 1. During Cycle 1, 3 pts experienced AEs that met Sponsor pre-defined DLT criteria: grade 3 fatigue on Day 15, gastroenteritis on Day 21, pneumonitis (due to infection) and hypotension on Day 5. None of these events were determined by the investigator to require treatment discontinuation, and all 3 pts remained on therapy. All 16 pts experienced at least 1 treatment emergent adverse event (TEAE) during cycles 1-4; 3 (19%) pts had at least 1 serious AE (SAE), with 2 (13%) related to Dara (gastroenteritis and pneumonitis). Eight (50%) pts had grade 3-4 TEAEs, with 6 (38%) related to Dara. The most commonly reported grade 3-4 TEAEs were neutropenia and thrombocytopenia (19% each), lymphopenia and leukopenia (13% each). Six (38%) pts experienced infections, including 1 Grade 3 SAE of gastroenteritis. There were no events of febrile neutropenia. There was no fatal outcome and no pt discontinued treatment due to TEAEs. Dara infusion related reactions (all Grade ≤2) were reported in 31% of pts during Cycles 1-4. To date, 11 pts had undergone mobilization with a median stem cell yield of 6.0 x 10⁶ (range 3.5-10.6) CD34+ cells/kg. All 16 pts in the safety run-in phase continue study treatment. Updated data and follow-up on these 16 pts will be presented at ASH.

Conclusion: No new safety signals were identified with the addition of Dara to RVd during the first 4 cycles of Dara-RVd in 16 pts with newly diagnosed MM. The overall safety profile was consistent with those previously reported for Dara and RVd. The first 4 cycles of safety run-in phase are completed, and all 16 pts continue therapy. Enrollment to the main phase of the randomized study is ongoing.